Glioma is a debilitating, often rapidly fatal cancer. Two recent genome wide association studies including one by our group discovered and confirmed three regions associated with risk of glioblastoma and other high grade glioma, and two additional regions that are likely to be associated with risk of lower grade glioma. Two of the glioma risk genes, TERT and RTEL1, are related to telomere maintenance. Polymorphisms (SNPs) in a third risk region in chromosome 9p21 (commonly deleted in glioblastoma) suggest a role for variation in the cell cycle gene CDKN2B in gliomagenesis. These represent the first consistent and highly significant genetic risk factors for glioma which provide a completely new perspective on glioma epidemiology and form a basis for this fifth grant cycle of our San Francisco Bay Area Glioma Study. In this application, we build on our extensive data and biospecimen repository and continuing recruitment at our site of adult glioma cases and controls supported through the Glioma International Case Control Study (R01CA139020). The Specific Aims are to: (1) Examine associations of patients'genotypic risk profile with meaningful histologic and molecular subtypes of glioma including IDH1 and IDH2 mutations, P53 and EGFR mutation status, and the ontological status of brain tumors related to gene expression. (2) Perform functional genomic experiments for glioma risk SNPs in CDKN2B (9p21), TERT, RTEL1, in vitro or model systems and in cell culture isolates (lymphocytes) derived from our epidemiologic recruitment and use bioinformatic analyses to discover effects of SNPs on transcription factor binding or disruption of gene function. (3) Conduct a thorough examination of the association of inherited variation in all known telomere-related genes with glioma risk through genotyping and analysis of a comprehensive set of candidate SNPs in telomere related genes in astrocytic glioma cases and controls. In addition to being part of the recently funded Glioma International Case Control study and the brain tumor SPORE program, our existing biorepository and data from this grant's previous 20 years of studies reduce costs for this proposed study. Our ongoing active collaborations with other glioma researchers ensure coordination and harmonization of results and maximize opportunities for rapid translation. PUBLIC HEALTH RELEVANCE: Primary brain cancers kill about 13,000 Americans a year and rank first among all cancer sites for average years of life lost. This study will help identify factors that cause these cancers. Enhanced understanding of these factors may provide targets for future interventions.